The objective is to understand the basis and biological significance of trophic interactions between corneal cells and trigeminal neurons. In previous studies from this laboratory, evidence was obtained to affirm the trophic effects of a corneal epithelium-derived Epithelial Neuronotrophic Factor (ENF) that prolongs survival and induces neurite outgrowth in trigeminal neurons, including its specificity and relation to corneal development. In this proposal, the emphasis is to utilize ENF as a probe to investigate (a) the physiologic factors that control corneal nerve regeneration, and (b) the molecular basis of axon induction and nerve regeneration in developing and mature trigeminal neurons. Reduced corneal sensitivity is associated with neurotrophic keratitis, herpetic keratitis, chemical injury and following intraocular surgery, and often predisposes the cornea to chronic desiccation, inflammation and persistent epithelial defects. Corneal nerve regeneration in these cases often take many years and is incomplete. Our aims are to determine (a) the role of ENF in corneal nerve regeneration by utilizing in vitro (compartmental culture of trigeminal neurons) and in vivo (surgical corneal denervation of rabbits) methods, (b) the physiologic and pharmacologic factors that regulate ENF secretion from corneal epithelium and their effects on corneal nerve regeneration (utilizing cultured corneal epithelial cells from rabbits) and (c) the stimulatory effects of ENF on the physiology of trigeminal neurons (by studying specific neuronal products such as substance P and collagens synthesized by cultured trigeminal neurons). These studies will provide information on the factors responsible for maintaining a healthy cornea-trigeminal trophic relationship and provide evidence for the therapeutic potential of ENF in accelerating corneal nerve regeneration.